Stability Study Through Water Activity Measurements for Dispensed Powdered Raw Materials.

BACKGROUND: Holding times for raw materials are relevant since they enable us to understand the allowable time that a raw material can be kept under ideal storage conditions before the start of the manufacturing process without its quality attributes being affected. The quantification of water activity can be used as an indicator of the microbiological, physicochemical, and organoleptic stability of a specimen, since low water activity retards autohydrolysis and microbiological growth. OBJECTIVE: The main purpose of this investigation was to test the stability of powdered raw materials for a maximum holding time of 8 days through water activity measurements. Thus microbiological, physicochemical, and organoleptic measurements were carried out in parallel and simultaneously to experimentally establish a relationship between the status of the water activity of processed raw materials and the microbiological, physicochemical, and organoleptic results. METHODS: The raw materials were stored for a maximum holding time of 8 days, in accordance with United States Pharmacopeia monographs. For all the raw materials tested, water activity measurements were performed using the dew point chilled-mirror method on days 0, 3, and 8. On days 0 and 8, microbiological, physicochemical, and organoleptic assessments were performed. RESULTS: It was established that under these storage conditions, the processed raw materials exhibited water activity below 0.60 during the entire holding time. However, there were statistically significant differences in water activity levels between days 0, 3, and 8 (ANOVA P < 0.05). Despite observing statistically significant differences between days, the microbiological, physicochemical, and organoleptic features were within specification at those water activity levels below 0.60. CONCLUSIONS: Water activity below 0.60 does not allow the growth of microorganisms, and the organoleptic and physicochemical features remain unperturbed. The results indicate that water activity can be used as an indicator of the microbiological load and chemical stability of the raw materials tested. HIGHLIGHTS: This research provides evidence that corroborates that water activity status may be used as a reliable indicator for the microbiological burden and physicochemical features of pharmaceutical material during stability studies.

Efficacy Comparison of an Automated Growth-Based System and Plate-Count Method on the Detection of Yeasts and Molds in Personal Care Products.

OBJECTIVE: The present investigation studies the efficacy of an automated growth-based system for a quantitative determination of Candida albicans and Aspergillus brasiliensis in several personal care products. The main purpose of this validation study was to prove that the alternative method's entire performance is not inferior to the conventional pour-plate method for a quantitative determination of yeasts and molds. Thus, a performance equivalence was established in accordance with the United Stated Pharmacopeia (USP-NF) Validation of Alternative Microbiological Methods ˂1223˃. METHODS: C. albicans and A. brasiliensis were pooled to use as inoculum (equivalent to 1.0 × 108 CFU/mL) in the suitability of the method test. PCP's preservatives were chemically neutralized leading to the yeast and mold recovery by means of the alternative microbiological method (AMM) and the pour-plate method. A correlation curve was generated for each PCP by plotting DTs relative to the corresponding log CFU values. RESULTS: Thirty PCPs have been tested for quantification of yeasts and molds using an AMM. An equivalence of results was made through the construction of correlation curves that allowed the establishment of numerically equivalent results between the enumeration data from the reference method (CFU) and the alternative method (Detection times, DTs). Thus, following the guidelines of USP Ch.1223, essential validation parameters were tested, such as equivalence of results (Correlation coeficient, CC >0.95), linearity (R2 >0.9025), accuracy (% recovery >70%), operating range, precision (CV <35%), ruggedness (one-way ANOVA, P > 0.05), specificity, LOD, and LOQ. CONCLUSION: It was shown that all the test results obtained from the alternative method were in statistical agreement with the standard plate-count method (PCM). Thus, this new technology was found to meet all the validation criteria needed to be considered for an alternative method for yeast and mold quantification in the PCPs tested. HIGHLIGHTS: In accordance with the United Stated Pharmacopeia (USP-NF) Validation of Alternative Microbiological Methods ˂1223˃, the implementation of alternative methods can offer benefits in execution and automation while improving accuracy, sensitivity, and precision and reduce the microbiological process time compared to the traditional ones.

Validation of a Rapid Microbiological Method for the Detection and Quantification of the Burkholderia cepacia Complex in an Antacid Oral Suspension.

BACKGROUND: Despite the broad adoption of Soleris® technology in the food industry as semiquantitative method, it is almost completely unexplored in the pharmaceutical industry as a quantitative method for quantification of Burkholderia cepacia complex (Bcc). OBJECTIVE: The efficacy of an automated growth-based system for a quantitative determination of the Bcc in an antacid oral suspension was studied. The main purpose of this validation study was to prove that the alternative method's entire performance is not inferior to the conventional method for a quantitative determination of Bcc. METHOD: The antacid oral suspension's preservatives were neutralized, leading to the Burkholderia complex's recovery by means of the alternative method and the reference method. A calibration curve was generated for each strain by plotting DTs relative to the corresponding log CFU values. An equivalence of results was done through the construction of calibration curves that allowed the establishment of numerically equivalent results between the enumeration data from the reference method and the alternative method. RESULTS: Thus following the guidelines of USP, essential validation parameters were shown, such as equivalence of results (CC >0.95), linearity (R2 >0.9025), accuracy (% recovery >70%), operating range, precision and ruggedness (DS <5 and CV <35%), specificity (inclusivity and exclusivity), limit of detection (LOD), and limit of quantification (LOQ). CONCLUSIONS: It was shown that all the test results obtained from the alternative method were in statistical agreement with the standard method. Thus this new technology was found to meet all the validation criteria needed to be considered as an alternative method for the quantification of the Burkholderia complex in the antacid oral suspension tested. HIGHLIGHTS: As outlined in USP chapter <1223> and demonstrated in this research the implementation of alternative methods can offer benefits in execution and automation while improving accuracy, sensitivity, and precision and can reduce the microbiological process time compared to the traditional ones.

Performance Equivalence and Validation of a Rapid Microbiological Method for Detection and Quantification of Yeast and Mold in an Antacid Oral Suspension.

Alternative and rapid microbiological methods can be effective replacements for more traditional plating approaches for ensuring quality and safety in the pharmaceutical industry. This article compares the efficacy of the Soleris automated method and the traditional plate-count method for the quantitative detection of yeasts and molds at three different microbial bioburden levels. Validation testing was carried out using an antacid oral suspension (aluminum hydroxide 4% + magnesium hydroxide 4% + simethicone 0.4%). Equivalence of data between detection time and colony-forming units was established for both the alternative and the conventional methodologies. Using probability of detection, linear Poisson regression, Fisher's test, and multifactorial analysis of variance (ANOVA), all results from the rapid method were shown to be in statistical agreement with the those of the reference plating procedures. The limits of detection and quantification were statistically similar for both methods (Fisher's exact test, P > 0.05), showing that the alternative method is not inferior in performance to the reference method. Essential validation parameters such as precision (standard deviation <5, coefficient of variance <35%), accuracy (>70%), linearity (R2 >0.9025), ruggedness (ANOVA, P < 0.05), operative range, and specificity were determined. It was shown that all the test results obtained using the alternative method were in statistical agreement with the those of the standard plate-count method. Thus, this new technology was found to meet all the validation criteria needed to be considered as an alternative method for yeast and mold quantification in the antacid oral suspension tested. However, taking into account that the present validation was carried out utilizing A. brasiliensis and C. albicans as suitable models for yeasts and molds and with an antacid oral suspension as a pharmaceutical matrix, further investigation will be required to qualify Soleris technology for other environmental isolates and recovery of these isolates from production batches.

Efecto de la fuerza de compresión sobre los atributos críticos de calidad en tabletas de liberación inmediata de furosemida / Effect of compression force on critical quality attributes of immediate release tablets of furosemide

RESUMEN La furosemida es un fármaco poco soluble en agua (0,01825 mg/mL). Debido a su baja solubilidad y baja permeabilidad, se ubica en la clase IV del Sistema de Clasificación Biofarmacéutica (BCS, por sus siglas en inglés). Se absorbe rápida pero incompletamente en el tracto gastrointestinal (GI). Actualmente, este fármaco se comercializa en tabletas, las que para su obtención deben ser sometidas a un proceso de compresión. La fuerza aplicada en dicha compresión puede influenciar algunas de las características de calidad del producto; por ello, la presente investigación estudia el efecto de la fuerza de compresión sobre los atributos críticos de calidad en el proceso de fabricación (dureza, friabilidad y desintegración) y en el producto terminado (uniformidad de dosificación y disolución) de comprimidos de furosemida. El efecto sobre la disolución se determinó por los factores de diferencia (f 1) y de similitud (f 2) de los perfiles de disolución y los parámetros de eficiencia de la disolución (ED) y tiempo medio de disolución (TMD), los cuales se calcularon con el software académico kinetDS®. Los resultados obtenidos permitieron definir el rango de la fuerza de compresión para el cual se obtuvo una ED superior al 85% y un TMD inferior a 7,5 min.

SUMMARY Furosemide is poorly water soluble drug (0.01825 mg/mL). Due to its low solubility and low permeability, it is labeled in class IV of the Biopharmaceutical Classification System (BCS). It is rapidly but incompletely absorbed from the gastrointestinal (GI) tract. Currently, this drug is marketed as tablets, which should be subjected to a compression process. The force applied in this compression can influence some of the quality characteristics of the product. Therefore, this investigation was carried out to determine the effect of compression force on the critical quality attributes of the product in process (hardness, friability and disintegration) and of the finished product (uniformity of dosage and dissolution). The effect on the dissolution was determined by the difference factor (f 1) and similarity factor f 2 ) of the dissolution profiles, the dissolution efficiency (ED) and mean dissolution time (TMD) parameters, which were calculated by kinetDS® academic software. The results obtained allowed to define the range of compression force for which the ED was higher than 85% and the TMD lower than 7.5 min.